Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum: Outcomes for patients with melanoma.
Authors: Lilit Karapetyan, Hassan Mohammed Abushukair, Aofei Li, Andrew David Knight, Ayah N. Al-Bzour, Ian Macfawn, Zachary Thompson, Ann Chen, Rebekah E. Dadey, Arivarasan Karunamurthy, Danielle Vargas De Stefano, Cindy Sander, Sheryl Kunning, Yana G. Najjar, Diwakar Davar, Jason J. Luke, William E. Gooding, Tullia C. Bruno, John M. M. Kirkwood, Walter J. Storkus
Journal: Journal of Clinical Oncology (2023)

9565 Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor immune microenvironment (TIME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokine/cytokine (TLS-kine) expression levels in melanoma patients (MEL PTs) by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with PT tumor clinicopathological and TIME characteristics. Methods: Levels of TLS-kines in PT sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas MEL cohort (TCGA-SKCM) and a Moffitt MEL cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed. Results: Serum of 95 PTs with MEL were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. Tumors with brisk/non-brisk tumor-infiltrating lymphocytes (TIL) vs. absence of TIL exhibited significantly higher levels of APRIL/TNFSF13 (p = 0.01), CCL19 (p = 0.01) and CXCL13 (p = 0.01). In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 transcripts was significantly associated with improved OS in TCGA-SKCM[n = 448](HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt MEL PTs [n = 134] (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL10 and CXCL13 transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). High coordinate expression of the TNFSF13/CXCL10/CXCL13 transcripts in MEL was correlated with an increased presence of naïve B cells, plasma B cells, CD8 + T cells, and M1 macrophages and decreased levels of M2 macrophages and mast cells as well as a reduced neural network gene signature. Conclusions: Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. PTs exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. MEL differentially expressed genes positively associated with high coordinate APRIL/CXCL10/CXCL13 expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Further investigation of TLS-kine expression profiles related to clinical outcomes is warranted.